Complex Study Design. Dr Ulrike Lorch MD FRCA FFPM

Transcription

1 Complex Study Design Dr Ulrike Lorch MD FRCA FFPM

2 Complex Designs Adaptive study design Fusion/Combined/ Umbrella protocols

3 Umbrella Protocol A number of conventional studies are contained in one single study protocol: Single Ascending Dose Food Effect Intensive cardiac safety assessments Drug Drug Interactions Multiple Ascending Dose Age/Gender comparisons Ethnic comparisons Proof of Concept Patient populations Ulrike Lorch

4 Adaptive study design One or more decision points are built into the trial design; The subsequent conduct following that decision point depends on the data observed to that point without undermining the validity and integrity of the trial Changes are made by design, and not on an ad-hoc basis; therefore, adaptation is a design feature aimed to enhance the trial, not a remedy for inadequate planning. Paul Gallo et al.: Adaptive Designs in Clinical Drug Development An Executive Summary of the PhRMA Working Group. Journal of Biopharmaceutical Statistics, 16: ,

5 The adaptive study design toolkit Objectives Decision making based on results as they emerge 2 Adaptive Features 1 Controls 3 Ulrike Lorch

6 Potential Benefits What are the benefits of using adaptive protocols? Do adaptive and umbrella protocols save time?

7 Benefits By continuous learning and early decision making By adjusting the study design taking into account data as it emerges Research is directed towards Meaningful assessments Collection of relevant data Research is Safe Cost effective Ethical

8 Rationalise and simplify Add what is essential Take away what is not necessary Analyse data as and when needed Limited analysis of samples taken Fewer dose levels More ECG Longer in-house stay Additional PK samples Dr Ulrike Lorch

9 Time savings Saves significant time & cost Saves time & cost Ulrike Lorch

10 Time Savings Total Actual Time Savings in 18 of 29 adaptive Studies* which saved time stratified by the type of adaptive features used: 10/14 umbrella studies Saved on average 77 (21-140) days 2/14 umbrella studies completed neutrally compared to conventional non-adaptive (sequential) design as adaptive design features were not used 2/14 umbrella studies delayed 21 days against planned schedule due to the need for substantial amendments (i.e. lack of adaptability) 8/15 non-umbrella studies Saved on average 33 (7-63) days *Lorch U, Berelowitz K, Ozen C, Naseem A, Akuffo E, Taubel J (2012) The practical application of adaptive study design in early phase clinical trials: a retrospective analysis of time savings. Eur. J. Clin. Pharmacol. 68: Ulrike Lorch

11 How can we write an adaptive study protocol that is sufficiently detailed, clear, systematic whilst allowing for flexibility and evolution? How can the layout facilitate ethical and regulatory review?

12 Simplicity

13 The adaptive study design toolkit Objectives Decision making based on results as they emerge 2 Adaptive Features 1 Controls 3 Ulrike Lorch

14 Clinical Study Protocol A set of rules and decision trees rather than detail Adaptive Features Boundaries 1 2 Study Progression Rules Controls Toxicity Rules 3 Ulrike Lorch

15 Ulrike Lorch Adaptive Features and their Boundaries Protocol Area Adaptive features Boundaries Investigational Medicinal Product (IMP) / Dose Timing / Scheduling Dosing regimens IMP formulation/mode of administration Overlap Sentinel/Sub-groups Starting dose Maximum exposure Maximum dose/exposure increments Maximum treatment frequency/duration Minimum data requirements for progression Reference to study specific toxicity rules Study Participants Assessments Methods/Analysis Sample size (cohort size, No. of cohorts) Selection criteria Safety, PK, PD, exploratory samples and assessments can be adjusted in nature, timing and extent Methods and or analysis may be optional Minimum/maximum size and No. of cohorts Nature, direction and extent of adaptability of selection criteria Minimum data requirements for progression Maximum extent Nature, timing, extent and purpose of adaptability Minimum data requirements for progression

16 Control Mechanisms Toxicity Rules Toxicity Study Progression Grade 1 Continue Reversible Frequency Grade 2 Non-serious Expected* Not reversible Frequency Reversible Frequency Unexpected* Not reversible Frequency Either one or a combination of the following: Non-serious Expected* 1. Continue Reversible Frequency Study suspended Not reversible Frequency Reversible Frequency 2. Explore dosing regimen further 3. Suspend further escalation/exploration 4. Explore lower exposure dosing regimen Grade 3 Unexpected* Not reversible Frequency Serious Frequency Grade 4-5 Serious Study suspended *As defined in the study protocol Within pre-determined observation period Per system Organ Class Ulrike Lorch

17 Control Mechanisms Study Progression Rules Single Dose 1 Minimum PK/PD Minimum Safety Single Dose 2 Minimum PK/PD Minimum Safety Single Dose 3 Minimum PK/PD Minimum Safety Single Dose 4 Minimum PK/PD Minimum Safety Minimum PK/PD Minimum Safety Multiple Dose 1 Minimum PK/PD Minimum Safety Patient Dose 1 Minimum PK/PD Minimum Safety Ethnic Comparison Dose 1 Minimum PK/PD Minimum Safety Food Effect Dose Drug-Drug Interaction = Exposure/Dose escalation = Progression to another study part Ulrike Lorch

18 How do we deal with adaptive changes? Do they need to be disseminated to REC/MHRA? In case of a combined protocol (i.e. the umbrella protocol), do we have to submit the results from the individual parts of the study before we are allowed to move forward to the next part? Do we need authorizations before proceeding?

19 *Medicines and Healthcare products Regulatory Agency (MHRA) / National Research Ethics Service (NRES), UK Ulrike Lorch

20 Clinical Study Protocol

21 Ethical Considerations Whatever the research context, the interests of participants come first. Their dignity, rights, safety and well-being must be the primary consideration in any research proposal, as well as in REC review. RECs must be assured that there are proportionate safeguards to protect people taking part in research * Are adaptive studies as safe as non-adaptive studies? How can a REC assess potential risks and their minimization when reviewing an adaptive study? How can Informed Consent for adaptive studies be provided effectively, avoiding amendments? *Governance arrangements for research ethics Committees: a harmonised edition, 9 May 2011, updated April 2012, last accessed 21 July pdf,

22 REC Remit Although RECs must be assured about the planned ethical conduct and anticipated risks and benefits of any proposed research, they are not responsible for enforcement if the research turns out to be unsafe or is not carried out as agreed. This responsibility rests with the relevant regulators or comparable bodies, as well as with the researchers employer and sponsor and with the care organisations where the research takes place [ ]. A REC need not reconsider the quality of the science, as this is the responsibility of the sponsor and will have been subject to review by one or more experts in the field (known as peer review ). The REC will be satisfied with credible assurances that the research has an identified sponsor and that it takes account of appropriate scientific peer review. A REC can expect to rely on established mechanisms for ensuring the proper conduct of the research at individual sites. Where others have a regulatory responsibility, a REC can expect to rely on them to fulfil it. If the law gives another body duties that are normally responsibilities of a REC according to this document, RECs do not duplicate them. For example, the Medicines and Healthcare products Regulatory Agency has the primary legal responsibility for considering the safety of the research it regulates. Governance arrangements for research ethics Committees: a harmonised edition, 9 May 2011, updated April 2012, last accessed 21 July pdf,

23 Safety Toxicity Rules Continuous Assessment Adaptive Boundaries Avoidance of unnecessary exposure Study Progression Rules Collection of necessary data only Flexibility to change if safety requires Ulrike Lorch

24 Informed Consent Divide Informed Consent for umbrella studies into relevant distinct parts/forms Give headlines of what may change and the boundaries Avoid description of technical or scheduling details Describe maximum potential risks and inconveniences Ulrike Lorch

25 Thank you